Neuronal dysfunction is the leading complication associated with diabetes. Diabetic patients experience both cognitive impairment and a collection of syndromes termed "diabetic neuropathies". Although many of the pathways involved in initiating hyperglycemic-induced neuronal degeneration have been identified, promising therapies directed at preventing and alleviating symptoms are still lacking. With funding from the DOD, we have identified several small molecules which both enhance neurogenesis and protect neurons from apoptosis. We propose to develop these molecules as new compounds to treat neuronal dysfunction in type 1 diabetes. In Phase 1, we will re-screen our leading compounds to determine which compounds protect neurons in diabetes-specific in vitro assays. We will then determine whether prophylactic administration of these compounds has an effect on cognitive impairment and early symptoms of diabetic polyneuropathy in a rat model of spontaneous type 1 diabetes. In addition, we will perform dose response, acute toxicity and pharmacokinetic studies. Based on these results, we will choose one lead compound for further studies. In Phase 2 we will determine whether the lead compound also acts therapeutically when given within a certain time period post onset of diabetes. We will expand toxicity studies and we will test the molecule in a variety of diabetic animal models. The end result of these studies will be the identification of one lead compound to be developed as an IND/therapy in the treatment of diabetic polyneuropathy and/or diabetic encephalopathy.